Altered Methylation Profile of Lymphocytes Is Concordant with Perturbation of Lipids Metabolism and Inflammatory Response in Obesity

Obesity is associated with immunological perturbations that contribute to insulin resistance. Epigenetic mechanisms can control immune functions and have been linked to metabolic complications, although their contribution to insulin resistance still remains unclear. In this study, we investigated the link between metabolic dysfunction and immune alterations with the epigenetic signature in leukocytes in a porcine model of obesity. Global DNA methylation of circulating leukocytes, adipose tissue leukocyte trafficking, and macrophage polarisation were established by flow cytometry. Adipose tissue inflammation and metabolic function were further characterised by quantification of metabolites and expression levels of genes associated with obesity and inflammation. Here we show that obese pigs showed bigger visceral fat pads, higher levels of circulating LDL cholesterol, and impaired glucose tolerance. These changes coincided with impaired metabolism, sustained macrophages infiltration, and increased inflammation in the adipose tissue. Those immune alterations were linked to global DNA hypermethylation in both B-cells and T-cells. Our results provide novel insight into the possible contribution of immune cell epigenetics into the immunological disturbances observed in obesity. The dramatic changes in the transcriptomic and epigenetic signature of circulating lymphocytes reinforce the concept that epigenetic processes participate in the increased immune cell activation and impaired metabolic functions in obesity.

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Adipose Tissue in Obesity-Related Inflammation and Insulin Resistance: Cells, Cytokines, and Chemokines

ISRN Inflammation ◽

10.1155/2013/139239 ◽

2013 ◽

Vol 2013 ◽

pp. 1-12 ◽

Cited By ~ 385

Author(s):

Kassem Makki ◽

Philippe Froguel ◽

Isabelle Wolowczuk

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Immune Cells ◽

Metabolic Regulation ◽

Immune Cell ◽

Suppressor Cells ◽

Cell Types ◽

Immune Functions ◽

Cytokines And Chemokines ◽

Wide Range

Adipose tissue is a complex organ that comprises a wide range of cell types with diverse energy storage, metabolic regulation, and neuroendocrine and immune functions. Because it contains various immune cells, either adaptive (B and T lymphocytes; such as regulatory T cells) or innate (mostly macrophages and, more recently identified, myeloid-derived suppressor cells), the adipose tissue is now considered as a bona fide immune organ, at the cross-road between metabolism and immunity. Adipose tissue disorders, such as those encountered in obesity and lipodystrophy, cause alterations to adipose tissue distribution and function with broad effects on cytokine, chemokine, and hormone expression, on lipid storage, and on the composition of adipose-resident immune cell populations. The resulting changes appear to induce profound consequences for basal systemic inflammation and insulin sensitivity. The purpose of this review is to synthesize the current literature on adipose cell composition remodeling in obesity, which shows how adipose-resident immune cells regulate inflammation and insulin resistance—notably through cytokine and chemokine secretion—and highlights major research questions in the field.

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Dysregulation of macrophage PEPD in obesity determines adipose tissue fibro-inflammation and insulin resistance

10.21203/rs.3.rs-57182/v1 ◽

2020 ◽

Author(s):

Vanessa Pellegrinelli ◽

Segio Rodriguez-Cuenca ◽

Christine Rouault ◽

Hanna Schilbert ◽

Sam Virtue ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Inflammatory Responses ◽

Vital Role ◽

Metabolic Dysfunction ◽

Collagen Turnover ◽

Metabolic Complications ◽

Genetic Ablation ◽

Metabolic Dysfunctions ◽

Inflammatory Macrophages

Abstract Fibrosis is a hallmark of adipose tissue (AT) dysfunction and obesity-associated insulin resistance that results from an impaired collagen turnover. Peptidase D (PEPD) plays a vital role in collagen turnover by degrading proline-containing dipeptides. Nevertheless, its specific function and importance in AT is unknown. GWAS identified the rs731839 variant in the locus near PEPD that uncouples obesity from insulin resistance and dyslipidaemia, thus indicating that defective PEPD might impair AT remodelling and exacerbate metabolic complications. Here we show that in human and murine obesity, PEPD expression and activity decrease in AT, coupled to the release of PEPD systemically. Both events, in turn, are associated with the accumulation of fibrosis in AT and insulin resistance. Using pharmacologic and genetic animal models of PEPD down-regulation, we show that whereas dysfunctional PEPD activity provokes AT fibrosis, it is the PEPD secreted by AT the main contributor to inflammation, insulin resistance and metabolic dysfunction. Also, PEPD originated in inflammatory macrophages (Mɸ), plays an essential role promoting fibro-inflammatory responses via activation of EGFR in Mɸ and preadipocytes. Using genetic ablation of pepd in Mɸ that prevents obesity-induced PEPD release, also averts AT fibro-inflammation and obesity-associated metabolic dysfunctions. Taking advantage of factor analysis, we have identified the coupling of prolidase decreased activity and increased systemic levels of PEPD as the essential pathogenic triggers of AT fibrosis and insulin resistance. Thus, PEPD produced by Mɸ qualifies as a biomarker of AT fibro-inflammation and a therapeutic target for AT fibrosis and obesity-associated insulin resistance and type 2 diabetes.

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Changes in abdominal subcutaneous adipose tissue phenotype following menopause is associated with increased visceral fat mass

Scientific Reports ◽

10.1038/s41598-021-94189-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Julie Abildgaard ◽

Thorkil Ploug ◽

Elaf Al-Saoudi ◽

Thomas Wagner ◽

Carsten Thomsen ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Insulin Sensitivity ◽

Visceral Fat ◽

Subcutaneous Adipose Tissue ◽

Immune Cell ◽

Whole Body ◽

Metabolic Dysfunction ◽

Adipocyte Hypertrophy ◽

Subcutaneous Adipose

AbstractMenopause is associated with a redistribution of adipose tissue towards central adiposity, known to cause insulin resistance. In this cross-sectional study of 33 women between 45 and 60 years, we assessed adipose tissue inflammation and morphology in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) across menopause and related this to menopausal differences in adipose tissue distribution and insulin resistance. We collected paired SAT and VAT biopsies from all women and combined this with anthropometric measurements and estimated whole-body insulin sensitivity. We found that menopause was associated with changes in adipose tissue phenotype related to metabolic dysfunction. In SAT, postmenopausal women showed adipocyte hypertrophy, increased inflammation, hypoxia and fibrosis. The postmenopausal changes in SAT was associated with increased visceral fat accumulation. In VAT, menopause was associated with adipocyte hypertrophy, immune cell infiltration and fibrosis. The postmenopausal changes in VAT phenotype was associated with decreased insulin sensitivity. Based on these findings we suggest, that menopause is associated with changes in adipose tissue phenotype related to metabolic dysfunction in both SAT and VAT. Whereas increased SAT inflammation in the context of menopause is associated with VAT accumulation, VAT morphology is related to insulin resistance.

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Adipose tissue inflammation and metabolic dysfunction: a clinical perspective

Hormone Molecular Biology and Clinical Investigation ◽

10.1515/hmbci-2013-0032 ◽

2013 ◽

Vol 15 (1) ◽

Cited By ~ 2

Author(s):

Charmaine S. Tam ◽

Leanne M. Redman

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Low Grade ◽

Metabolic Dysfunction ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation ◽

Proinflammatory Mediators ◽

Low Grade Inflammation

AbstractObesity is characterized by a state of chronic low-grade inflammation due to increased immune cells, specifically infiltrated macrophages into adipose tissue, which in turn secrete a range of proinflammatory mediators. This nonselective low-grade inflammation of adipose tissue is systemic in nature and can impair insulin signaling pathways, thus, increasing the risk of developing insulin resistance and type 2 diabetes. The aim of this review is to provide an update on clinical studies examining the role of adipose tissue in the development of obesity-associated complications in humans. We will discuss adipose tissue inflammation during different scenarios of energy imbalance and metabolic dysfunction including obesity and overfeeding, weight loss by calorie restriction or bariatric surgery, and conditions of insulin resistance (diabetes, polycystic ovarian syndrome).

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Inflammation and impaired adipogenesis in hypertrophic obesity in man

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00377.2009 ◽

2009 ◽

Vol 297 (5) ◽

pp. E999-E1003 ◽

Cited By ~ 162

Author(s):

Birgit Gustafson ◽

Silvia Gogg ◽

Shahram Hedjazifar ◽

Lachmi Jenndahl ◽

Ann Hammarstedt ◽

...

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Subcutaneous Adipose Tissue ◽

Molecular Mechanisms ◽

Whole Body ◽

Preadipocyte Differentiation ◽

Metabolic Complications ◽

Adipose Cell ◽

Subcutaneous Adipose ◽

Adipose Cell Size

Obesity is associated mainly with adipose cell enlargement in adult man (hypertrophic obesity), whereas the formation of new fat cells (hyperplastic obesity) predominates in the prepubertal age. Adipose cell size, independent of body mass index, is negatively correlated with whole body insulin sensitivity. Here, we review recent findings linking hypertrophic obesity with inflammation and a dysregulated adipose tissue, including local cellular insulin resistance with reduced IRS-1 and GLUT4 protein content. In addition, the number of preadipocytes in the abdominal subcutaneous adipose tissue capable of undergoing differentiation to adipose cells is reduced in hypertrophic obesity. This is likely to promote ectopic lipid accumulation, a well-known finding in these individuals and one that promotes insulin resistance and cardiometabolic risk. We also review recent results showing that TNFα, but not MCP-1, resistin, or IL-6, completely prevents normal adipogenesis in preadipocytes, activates Wnt signaling, and induces a macrophage-like phenotype in the preadipocytes. In fact, activated preadipocytes, rather than macrophages, may completely account for the increased release of chemokines and cytokines by the adipose tissue in obesity. Understanding the molecular mechanisms for the impaired preadipocyte differentiation in the subcutaneous adipose tissue in hypertrophic obesity is a priority since it may lead to new ways of treating obesity and its associated metabolic complications.

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B Lymphocytes and Adipose Tissue Inflammation

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.119.312467 ◽

2020 ◽

Vol 40 (5) ◽

pp. 1110-1122 ◽

Cited By ~ 1

Author(s):

Prasad Srikakulapu ◽

Coleen A. McNamara

Keyword(s):

Adipose Tissue ◽

B Cell ◽

Immune Cells ◽

Immune Cell ◽

Metabolic Dysfunction ◽

Adipose Tissue Inflammation ◽

Cell Type ◽

Tissue Inflammation ◽

B Cell Subsets

The immune system plays an important role in obesity-induced adipose tissue inflammation and the resultant metabolic dysfunction, which can lead to hypertension, dyslipidemia, and insulin resistance and their downstream sequelae of type 2 diabetes mellitus and cardiovascular disease. While macrophages are the most abundant immune cell type in adipose tissue, other immune cells are also present, such as B cells, which play important roles in regulating adipose tissue inflammation. This brief review will overview B-cell subsets, describe their localization in various adipose depots and summarize our knowledge about the function of these B-cell subsets in regulating adipose tissue inflammation, obesity-induced metabolic dysfunction and atherosclerosis.

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Macrophages as Key Players during Adipose Tissue–Liver Crosstalk in Nonalcoholic Fatty Liver Disease

Seminars in Liver Disease ◽

10.1055/s-0039-1687851 ◽

2019 ◽

Vol 39 (03) ◽

pp. 291-300 ◽

Cited By ~ 3

Author(s):

Hannelie Korf ◽

Markus Boesch ◽

Lore Meelberghs ◽

Schalk van der Merwe

Keyword(s):

Adipose Tissue ◽

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Disease Progression ◽

Fatty Liver Disease ◽

Metabolic Profile ◽

Cell Activation ◽

Immune Cell ◽

Nonalcoholic Fatty Liver

AbstractNonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in Western countries that could lead to serious health problems including liver failure, cancer, or death. The term NAFLD includes a spectrum of disease states with histological features ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). A key aspect within this research field is the identification of pathogenic factors that trigger inflammation, thus fueling the transition from nonalcoholic fatty liver to NASH. These inflammatory triggers may originate from within the liver as a result of innate immune cell activation and/or hepatocyte injury. Additionally, they may originate from other sites such as adipose tissue or the intestinal tract. In the current review, the authors will primarily focus on events within adipose tissue which may be of importance in triggering the disease progression. They specifically focus on the role of adipose tissue macrophages during NAFLD pathogenesis and how microenvironmental factors may shape their metabolic profile. They further dissect how redirecting the macrophage's metabolic profile alters their immunological functions. Finally, they discuss the opportunities and challenges of targeting macrophages to interfere in disease progression.

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Neuroimmune Semaphorin 4A in Cancer Angiogenesis and Inflammation: A Promoter or a Suppressor?

International Journal of Molecular Sciences ◽

10.3390/ijms20010124 ◽

2018 ◽

Vol 20 (1) ◽

pp. 124 ◽

Cited By ~ 4

Author(s):

Apoorva Iyer ◽

Svetlana Chapoval

Keyword(s):

Cell Activation ◽

Immune Cell ◽

Fine Tuning ◽

Breast Cancers ◽

Immune Functions ◽

Immune Cell Activation ◽

Important Regulator ◽

And Function ◽

Axon Guidance Molecule ◽

Guidance Molecule

Neuroimmune semaphorin 4A (Sema4A), a member of semaphorin family of transmembrane and secreted proteins, is an important regulator of neuronal and immune functions. In the nervous system, Sema4A primarily regulates the functional activity of neurons serving as an axon guidance molecule. In the immune system, Sema4A regulates immune cell activation and function, instructing a fine tuning of the immune response. Recent studies have shown a dysregulation of Sema4A expression in several types of cancer such as hepatocellular carcinoma, colorectal, and breast cancers. Cancers have been associated with abnormal angiogenesis. The function of Sema4A in angiogenesis and cancer is not defined. Recent studies have demonstrated Sema4A expression and function in endothelial cells. However, the results of these studies are controversial as they report either pro- or anti-angiogenic Sema4A effects depending on the experimental settings. In this mini-review, we discuss these findings as well as our data on Sema4A regulation of inflammation and angiogenesis, which both are important pathologic processes underlining tumorigenesis and tumor metastasis. Understanding the role of Sema4A in those processes may guide the development of improved therapeutic treatments for cancer.

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OGT suppresses S6K1-mediated macrophage inflammation and metabolic disturbance

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1916121117 ◽

2020 ◽

Vol 117 (28) ◽

pp. 16616-16625

Author(s):

Yunfan Yang ◽

Xiruo Li ◽

Harding H. Luan ◽

Bichen Zhang ◽

Kaisi Zhang ◽

...

Keyword(s):

Cell Activation ◽

Immune Cell ◽

Nutrient Sensing ◽

Metabolic Disturbance ◽

Whole Body ◽

Metabolic Dysfunction ◽

Peripheral Tissues ◽

Mtorc1 Signaling ◽

Whole Body Metabolism ◽

Glcnac Transferase

Enhanced inflammation is believed to contribute to overnutrition-induced metabolic disturbance. Nutrient flux has also been shown to be essential for immune cell activation. Here, we report an unexpected role of nutrient-sensingO-linked β-N-acetylglucosamine (O-GlcNAc) signaling in suppressing macrophage proinflammatory activation and preventing diet-induced metabolic dysfunction. Overnutrition stimulates an increase inO-GlcNAc signaling in macrophages.O-GlcNAc signaling is down-regulated during macrophage proinflammatory activation. SuppressingO-GlcNAc signaling byO-GlcNAc transferase (OGT) knockout enhances macrophage proinflammatory polarization, promotes adipose tissue inflammation and lipolysis, increases lipid accumulation in peripheral tissues, and exacerbates tissue-specific and whole-body insulin resistance in high-fat-diet-induced obese mice. OGT inhibits macrophage proinflammatory activation by catalyzing ribosomal protein S6 kinase beta-1 (S6K1)O-GlcNAcylation and suppressing S6K1 phosphorylation and mTORC1 signaling. These findings thus identify macrophageO-GlcNAc signaling as a homeostatic mechanism maintaining whole-body metabolism under overnutrition.

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The role of innate immune cells in obese adipose tissue inflammation and development of insulin resistance

Thrombosis and Haemostasis ◽

10.1160/th12-09-0703 ◽

2013 ◽

Vol 109 (03) ◽

pp. 399-406 ◽

Cited By ~ 56

Author(s):

Triantafyllos Chavakis ◽

Jindrich Chmelar ◽

Kyoung-Jin Chung

Keyword(s):

Insulin Resistance ◽

Adipose Tissue ◽

Immune Cells ◽

Cytotoxic T Cells ◽

Innate Immune ◽

Low Grade ◽

Innate Immune Cells ◽

Metabolic Complications ◽

Adaptive Immune Cells

SummaryObesity is characterised by a chronic state of low-grade inflammation in different tissues including the vasculature. There is a causal link between adipose tissue (AT) inflammation and obesity-related metabolic complications, such as the development of insulin resistance and subsequently of type 2 diabetes. Intense efforts in the recent years have aimed at dissecting the pathophysiology of AT inflammation. The role of both innate and adaptive immune cells, such as macrophages or cytotoxic T cells in AT inflammation has been demonstrated. Besides these cells, more leukocyte subpopulations have been recently implicated in obesity, including neutrophils and eosinophils, mast cells, natural killer cells or dendritic cells. The involvement of multiple leukocyte subpopulations underlines the complexity of obesity-associated AT inflammation. In this review, we discuss the role of innate immune cells in AT inflammation, obesity and related metabolic disorders.

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